10-{8 4-({107 -Hydroxy alkyl)-1-piperazimyl{9 -dibenzo (h,f) oxofins and thiepins and acetyl esters thereof

ABSTRACT

Tricyclic enamine compounds of the formula:   WHEREIN A is oxy, thio, lower alkylimino, or ethylidene; one of X1 and X2 is hydrogen and the other is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfonyl, lower alkylsulfamoyl, di(lower)alkylsulfamoyl, lower alkanoylamino, trifluoromethyl, nitro or amino; X3 is hydrogen, lower alkyl or phenyl(lower)alkyl and Nz is a 5 to 7-membered cyclic amino group. These compounds are useful as psychotropic agents, particularly as tranquilizers.

United States Patent 91 Umio et al. 5] Dec. 23, 1975 10-{4-(6i-HYDR0XY 3,451,264 lll969 Viterbo 260/268 TR ALKYLHP'PERAZMU'DBENZO 3'32333 11:33? 1""="'I"'| 523/5231:

, as ul'sl C a Oxoms THIEPINS AND 3,600,39l 8/l97l Mastursi et al. 260/268 TR ESTERS THEREOF 3,681,354 5/1972 Mastursi et al. 260/268 TR Inventors: Suminori Umio, Kawanishi; [kilo Ueda, Yao; Yoshinari Sato, lkeda; Shizuo Maeno, Osaka, all of Japan Fujisawa Phannaceutical Co., Ltd., Japan Filed: Nov. 14, 1972 Appl. No.: 306,394

Related US. Application Data Assignee:

Continuation of Ser. No. 874,710, Nov. 6, I969, abandoned, which is a continuation-in-part of Ser.

No. 762,998, Sept. 26, I968, abandoned.

Foreign Application Priority Data Oct. 6, 1967 Dec. 20, I967 Jan. 29, 1968 Feb. 28, I968 Mar. 4, 1968 Mar. 19, l968 Apr. 10, I968 June 24, 1968 Japan.... Japan....

Japan References Cited UNITED STATES PATENTS Japan 42-64540 Japan 43-12773 43-13966 Japan 43-44033 Jilek 260/268 TR Corts 260/268 TR OTHER PUBLICATIONS Umio et al., 1, Chem. Abstr. Vol. 74 (1971) abstracting Japan 70 29,830. Col. 22880s Umio et al. Il, Chem. Abstr. Vol. 75, Col. 7684721 and 76849c abstracting Japan 71 21,39], Japan 71 21,392.

Umio et al. Chem. Abstr. Vol. 71, Col. ll2976v abstracting Gennan 1,801,523 (June 69).

Primary Examiner-Paul M. Coughlan, Jr. Attorney, Agent, or Firm-Jordan B. Bier-man; Linda 0. Bierman; Kenneth J. Stempler wherein A'is oxy, thio, lower dlkylimino, or ethylidene; one of X and X, is hydrogen and the other is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfonyl, lower alkylsulfamoyl, di(lower)alkyl ulfamoy1, lower alkanoylamino, trifluoromethyl, nitroi or amino; X, is hydrogen, lower alkyl or phenyl(lower)alkyl and N, ha 5 to 7-membered cyclic amino group. These compounds are useful as psychotropic agents, particularlyas tranquilizers.

11 Claims, N0 Drawings lower)alkyl-l-piperazinyl]-l l-lower alkyl or phenyl(- lower)alkyldibenz[b,f]oxepin, lO-morpholinodibenz[b,f]oxepin, lO-morpholino-l l-lower lower alkoxy(lower)alkyl, lower alkanoy|(lower)alkyl, lower alkanoyloxy(lower)alkyl, hydroxycarbonyl(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, hydroxy(- lower)alkoxy(lower)alkyl, carbamoyl(lower)alkyl, phenyl(lower)alkyl, phenoxy(lower)alkyl, phenyl(- lower)alkoxy(lower)alkyl or benzoyloxy(lower)alkyl. Further, the phenyl moiety in the substituent at the 4-position of the piperazinyl or diazepinyl group may not have more than three halogen, lower alkyl and/or lower alkoxy groups and each of the pyrrolidinyl, piperidino, piperazinyl, diazepinyl and morpholino groups may not be substituted with more than three methyl groups.

In addition, further examples may include the corresponding 2 or 8-halo, lower alkyl, lower alkoxy, lower alkylthio, lower alkanesulfonyl, lower alkylsulfamoyl, di-(lower)alkylsulfamoyl, lower alkanoylamino, trifluoromethyl, nitro or amino derivative. Further examples may include the corresponding dibenzo[b,f]thiepiri, S-lower alkyl-SH-dibenz[b,f]azepine or dibenzo[a,dlcycloheptene derivative.

It has been found that the compounds (I) and their salts (i.e. pharmaceutically acceptable acid addition salts and quaternary ammonium salts) show characteristic psychotropic and neurotropic activity such as central nervous system depressing activity, antihistaminic activity, analgesic activity, antiemetic activity and spasmolytic activity. Their tranquilizing action is particularly notable.

Accordingly, a basic object of the present invention is to embody the compounds (I) and their salts. Another object of this invention is to embody the compounds (I) and their salts having psychotropic activity. Another object of the invention is to embody the compounds (I) and their salts useful as tranquilizers. A further object of the invention is to embody a process for preparing the compounds (I) and their salts. These and other objects will be apparent from the subsequent descriptions to those conversant with the art to which the present invention pertains.

According to the present invention, the compounds [I] may be prepared by various procedures. The fundamental procedure is represented by the following formulae:

[II 1 I j z Xg-N'z 3 Hz X wherein A, X X X and N are each as defined above and X is hydrogen, alkali metal (e.g. lithium, sodium) or halomagnesium (e.g. chloromagnesium, bromomagnesium, iodomagnesium The starting compound [I] may be prepared by a conventional method [e.g. Chemical Abstracts, 62, l62l5 (1965); ibid., 63, 2952 (I966); J. Pharm. Soc. Japan, 74, 426 (1954)] or any such similar method.

The reaction is carried out by treating the compound [ll] with the reagent [III] in the presence ofa condensing agent such as a Lewis acid (e.g. titanium chloride, aluminum chloride, ferric chloride, boron chloride, tin chloride, zinc chloride, zirconium chloride, arsenic chloride, antimony chloride), preferably in a solvent (e.g. benzene, toluene, xylene, hexane). When the reagent [III] is a liquid, it may also serve as a solvent. The reaction temperature is not restricted to a particular temperature. The reaction is often carried out at room temperature or upon heating.

The application of the above fundamental procedure may be unsuitable for the preparation of some compounds, because of reasons such as poor yields, unavailability of the starting compounds, or because of the expense of the reagent. In such cases, an alternative procedure may be adopted.

One of the alternative procedures is shown in the following scheme:

wherein A, X X, and X, are each as defined above, X is hydrogen or one or two methyl group, X, is a reactive ester residue such as halogen (e.g. chlorine, bromine, iodine), sulfuric acid residue or sulfonic ester residue (e.g. methanesulsulfonyloxy, toluenesulfonyloxy), R is 5 lower alkyl (e.g. methyl, ethyl, propyl), lower alkenyl (e.g. allyl, butenyl), lower alkynyl (e.g. propargyl), lower alkanoyl (e.g. acetyl, propionyl), lower alkoxy carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl), hydroxy(lower)alkyl (e.g. hydroxyethyl, hydroxypropyl), lower alkoxy(lower)alkyl (e.g. methoxyethyl, ethoxyethyl, methoxypropyl), lower alkanoyl(lower)alkyl (e.g. acetylmethyl, acetylethyl, propionylethyl, propionylbutyl), lower alkanoyloxy(lower)alkyl (e.g. acetyloxyethyl, acetyloxypropyl), alkoxycarbonyl(lower)alkyl (e.g. methoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonylpropyl), hydroxy(lower- )alkoxy(lower)alkyl (e.g. hydroxymethoxymethyl, hydroxyethoxyethyl), carbamoyl(lower)alkyl (e.g. carbamoylmethyl, carbamoylethyl), phenyl(lower)alkyl (e.g. benzyl, phenethyl), phenoxy(lower)alkyl (e.g. phenoxymethyl, phenoxyethyl). phenyl( lower)alkoxy(- lower)alkyl (e.g. benzyloxymethyl, benzyloxyethyl), bcnzoyloxy(lower)alkyl (e.g. benzoyloxymethyl, benzoyloxyethyl or phenyl( lower)alkanoyloxy( lower)alkyl (eg. phenaeetylethyl, phenacetylpropyl), in which the phenyl group may not have more than three halogen atoms (e.g. chlorine, bromine, iodine), lower alkyl groups (e.g. methyl, ethyl, propyl) and/or lower alkoxy groups (e.g. methoxy, ethoxy, propoxy and n is either 2 or 3.

The reaction is carried out by treating the compound [l'] with the reagent [IV] in the presence of a basic material such as alkali metal (e.g. sodium, potassium, lithium) or alkaline earth metal (e.g. calcium), their hydroxide, hydride, amide, alkoxide or carbonate or an organic tertiary amine (e.g. pyridine, triethylamine, dimethylaniline), preferably in a solvent (e.g. methanol, ethanol, ether, benzene, acetone, dimethylformamide, diemthylsulfoxide). The reaction temperature is dependent upon the starting compound [l], the reagent [lV I, the basic material and the solvent employed. The reaction is usually carried out at a temperature around the boiling point of the solvent,

Another alternative procedure is shown in the following scheme:

3 t I I] CH CH-R CH 11 X aa cmomn (CH Y I E GHOH OH wherein A, X X X X and n are each as defined above and R is hydrogen or lower alkyl (egimethyl, ethyl, propyl).

The reaction is carried out by treating the compound [l'! with the reagent [V], usually in a solvent (e.g. methanol, ethanol, acetone, chloroform, dioxane, nhexane, benzene, toluene, xylene). The reaction product is the compound [l'| contaminated with the compound [l"] and readily separated into each component by a conventional separation procedure.

Another alternative procedure is shown in the following scheme:

l 7 [I 1 00-11 {1 us R 3 A l. l l 7 2 '1 2 N\ 5 /N x (0112M l X5 (GI-[2M X5 \NJ n [I9] lU-GO-OR [1 N-GH -OH wherein X,, X X X,,, A and n are each as defined above, A" is lower alkylene (e.g. methylene, ethylene, propylene, trimethylene) and R is lower alkyl (e.g. methyl, ethyl, propyl. isopropyl, butyl phenyl or phenyl(lower)alkyl (e.g. benzyl, phenethyl), the phenyl group having no more than three halogen atoms, lower alkyl groups and/or lower alkoxy groups.

The reaction is carried out by treating the compound [l""] with the reagent UV] or its reactive derivative at the carboxyl group in a solvent (e.g. ether, acetone,

55 dioxane, acetonitrile, chloroform, ethylene chloride,

tetrahydrofuran, ethyl acetate, pyridine), if needed, in the presence of a basic material such as alkali hydroxide (cg. sodium hydroxide, potassium hydroxide). al- TE T 2 kali carbonate (eg sodium carbonate, potassium carbonatc) alkali bicarbonate (cg. sodium bicarbonate, Apomorphme Antagonism test In mt potassium bicarbonate). trialkylaminc (e.g. triethylam- Grou of SD-JCL strain male rats, each group inc. tripropylamine) f pyridine a -gpyridin 5 consisting of animals, received an aqueous solution picoline. lutidine). Examples of the reactive derivative or a 0.5% CMC suspension of the test compound by a ol'thc reagent [Vl] include acid halide. acid anhydride, subcutaneous route. Thirty minutes after a dose of the amide, ester. test compound under investigation, each rat received A still further procedure is shown in the following an intraperitoneal injection of l.() mg/kg of apomorscheme: m phine hydrochloride. After 10. and 30 minutes the V 15 16 N x 2 3: wherein A. X and N are each as defined above. animals were observed for several minutes by an ob- The reaction is carried out by treating the compound 2 server. Absence of the typical growing movements l'-") with a reducing agent such as the combination of occurring after injection of apomorphine was interan organic acid (e.g. acetic acid) and a metal (e.g. zinc. preted as a test compound effect (positive effect). The

iron) in a solvent (cg. methanol, ethanol, ether, acetic ED value was calculated from the mean positive peracid), or subjecting said compound to catalytic reduccent at each dose level by the Litchfield-Wilcoxon tion in the presence of a catalyst (e.g. platinum oxide. method.

palladium oxide. Raney nickel) in a solvent (eg. meth b. The test was carried out as described above but an anol. ethanol, ether, dioxane). aqueous solution of apomorphine was intravenously Compound (I) prepared in the above described manadministered to each rat at a dose of L25 mg/kg. The

ner. may be converted into its acid salt or quaternary ED value was calculated as above.

ammonium salt by a conventional method. Examples of The results are shown in Table 2.

the salts include mineral acid salts (cg. hydrochloride, Table 2 sulfate. nitrate. phosphate), organic acid salts {c.g.

acetate. propinate. succinate, oxalate, maleate, tar- 5? ii tratc. fumalate. citrate, phenolphthalin salt) and qua- As stated above, the compounds (I) and their salts $322211p lg i show psychotropic and neurotropic activity such as 8- mm.m. n. 4 n28 central nervous system depressing activity. antihista- 4O dlhfinllhflnwpm I I. I I t. .t I t. t. -t l0-I4-(2-Hydroxyethyl)-l'p|pcraz|nyl|- 0.53 mime ac iv|ty, aria gesrc ac lVl y, an ieme 1c ac l y dihenmlhmhicpin and spasmolytlc activity. Some of the test results by 8:Chloru-l0'| 4-(Z-hydroxyethyU- 0.22 which said activities are evidenced are shown below. gfgf l f l orproma/lnc 0.74 6.8

TEST 1 4S TEST 3 Sleeping time prolongation I Groups of [CRJCL Strain male mice each g p Depression of conditioned avoldance response consisting of l2 animals, received an aqueous solution AS the test m C t ain al rats w e or a 0.5% CMC en i n f th te t om ou d b a conditioned so as to produce more than 90% response. subcutaneous method. Thirty minutes thereafter, each The rats were administered the test compound by a animal was given intraperitoneally 90 mg/kg of methylsubcutaneous or oral route and received white noise as hexabital sodium. The duration of sleep was measured, Condit oned stimulus and electroshock as uncondiand the ED value was cal ulated b the Litchfield tioned stimulus. The conditioned avoidance response Wilcoxon method taking as I00 percent the three time 5s was observed at intervals from 30 to minutes after prolongation compared with the control. the administration. This was compared with the control The results are shown in Table 1. carried out on the same animals during the preceding Table 1 day to calculate the depression rate, from which the ED value was determined by graphing the mean demy pression rate at each dose level.

. 60 lll-(4-Methyl-l-plperazmyll 0.13 The results are shown in Table 3. dihcnzolbjlthicpin l0-(4-Mcthyl-l-pipcrazinylk 0.26 Table 3 dibenzl b.l'loxepin X-(hloro-lO-l4mcthyll-piperayinyl 0. l 7 Test compound EDM (mg/kg) dibenzol lmflthiepin Subcu- Oral X-(hloro- I0-l d-methyll -piperazinyl 0.32 (,5 taneous dibcml lmfloxcpin K-(hlorol 0-1 4-( 2-hydroxycthyl l 0.25 f -l hyll pipc uziny 0.2 5 2.0 pipcflinyl ldibcnzol bJIthiepin -"I l P I04 4-( I-Hydroxycthyl I pipcra:1inyl l- 0.4 X-(hloro-l0-(4-mcthyll pipcrazinyl 0.054 L06 dihcmol h.f]thicpin dibcmol hflthiepin K-Chlurol0-[ 4-( Z-hydruxycthyl l 0.5 t l-Chlurol0( 4-rncthyll pipera7.inyl 0.055 0.24 pipcralinyl Idihcnzl bfloxcpin dihenzl h.l'loxcpin ('hlurproma/inc 0.84 (hlorpromalinc 0.45 5.74

1 1 TEST 4 Acute toxicity The test compound was subcutaneously administered to groups of dd strain male mice, each group consisting of IO animals. Death was observed for 3 days after administration, and the LD value was calculated according to the Litchfield-Wilcoxon method.

The results are shown in Table 4.

piper-.uinyl )dihcnll hJ'loxcpin ('hlorpromavinc Although the compounds [I] generally have the above useful activities, the following compounds are particularly potent: l( 4-methyll -piperazinyl dibenz[ b,f]oxepin, 8-chlorol 0-( 4-methyllpiperazinyl )dibenz[ b,f]oxepin, l0-[4-( Z-hydroxyethyl l -piperazinyl ]dibenz[b,f]oxepin, 8-chloro- 1 (H4 (Z-hydroxyethyh- 1 -piperazinyl ]dibenz[ b,f]oxepin, l0- (4-methyll-piperazinyl )dibenzo[ b,f]thiepin, 8-chloro- 10-(4-methyl-l-piperazinyl)dibenzo[b,f]thiepin, l0- [4-( 2-hyd roxyethyl l-piperazinyl ]dibenzo[ b,f]thiepin, 8-chlorol 0-[4-(2-hydroxyethyl)-l-piperazinyl1- dibenzo[b,f]thiepin, etc.

Because of the possession of the above described activities, the compounds [I] and their non-toxic salts are useful as tranquilizers.

The compounds [I] andtheir non-toxic salts can be administered by conventional methods, with conventional types of unit dosages and with conventional pharmaceutical carriers to produce a tranquilizing effeet in human beings.

Thus, they can be used in the form of pharmaceutical preparations, which contain them in admixture with a pharmaceutical organic or inorganic carrier material suitable for enteral or parenteral applications. Oral administration by the use of tablets, capsules or in liquid form, such as suspensions, solutions or emulsions, is particularly advantageous. When formed into tablets, the conventional binding and disintegrating agents used in therapeutic unit dosages can be employed. Examples of binding agents include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Examples of disintegrating agents include corn starch, keratin, colloidal silica and potato starch. When administered as liquids the conventional liquid carriers can be used.

The unit dosage or therapeutically effective quantity of the compounds (I) and their non-toxic salts for human beings can vary over wide limits such as about 0.! milligram to 50 milligrams. The upper limit is limited only by the degree of effect desired and economic considerations. For oral administration it is preferable to employ about 1 milligram to about It) milligrams of the therapeutic agent per unit dosage. Animal experiments indicate that about 1 to l0 milligram dosages administered orally four times daily, as needed, will provide a preferred daily dosage. Of course, the dosage of the particular therapeutic agent used can vary considerably, depending on the age of the patient and the degree of therapeutic effect desired. Each unit dosage form of the novel therapeutic compounds can contain from about 5% to of the novel therapeutic agents by weight of the entire composition, with the remainder comprising conventional pharmaceutical carriers. The term pharmaceutical carrier" is intended to include non-therapeutic materials which are conventionally used with unit dosage and includes fillers, diluents, binders, lubricants, disintegrating agents and solvents. It is possible, however, to administer the novel therapeutics, i.e. the pure compounds, without the use of a pharmaceutical carrier.

Practical and presently preferred embodiments of this invention are illustratively shown in the following examples.

EXAMPLE I A. A solution of 4.54 g of dibenzo[b,f]thiepinlO( 1 lH)-one and 6.00 g of l-methylpiperazine is about 80 ml of n-hexane was stirred in a nitrogen atmosphere while cooling. A solution of L9 g of titanium tetrachloride in 50 ml of n-hexane was added to the above described solution over a 40 minute period. The resulting mixture was stirred at room temperature for 1 hour and heated at reflux for 48 hours. The reaction mixture was filtered. The collected material was washed with n-hexane. The filtrate and the washings were combined together and concentrated. The residue was chromatographed on alumina and eluted with benzene. The eluate was concentrated to give 3.6 g of l0-(4-methyl-lpiperazinyl) dibenzo-[b,f]thiepin. Oxalate, M.P. 233C (decomp). Maleate, melting point 221C (decomp).

B. A solution of 3.8 g of titanium tetrachloride in 50 m1 of anhydrous benzene was added dropwise to a solution of 9.l g of dibenzo[b,f]thiepin-l0(l lH)-one and l2.2 g of l-methylpiperazine in 200 ml of anhydrous benzene. The addition took place with continual stirring and cooling. The reaction mixture was stirred at room temperature for l hour and heated at reflux for 15 hours. The reaction mixture was then filtered. The collected material was washed with benzene. The filtrate and the washings were combined together and concentrated. The resulting oily substance was allowed to stand overnight, and the solidified material was recrystallized from ethanol to give 8.5 g of l0-(4methyll-piperazinyl)dibenzo[b,f]-thiepin. M.P. 109 to l l2C. Oxalate, melting point 233C (decomp).

C. A solution of 200 mg of titanium tetrachloride in 5 ml of anhydrous benzene was added dropwise to a cooled solution of 500 mg of 8-methyldibenzo[b,f]thiepin-lO( l lH)-one and 1.0 g of l-methylpiperazine in 10 ml of anhydrous benzene. The addition took place over a 40 minute period attended by stirring and cooling in nitrogen gas. The resultant mixture was stirred at the same temperature for a period of time and then heated at reflux for 20 hours. The reaction mixture was cooled and filtered. The filtrate was dried and concentrated.

The residue was chromatographed on alumina and eluted with benzene and then ethanol. The ethanol eluate was concentrated to give 400 mg of B-methyll0-(4-methyll -piperazinyl)dibenzo[b,f]thiepin. Maleate, melting point 227C (decomp.).

D. A solution of 1.9 g of titanium tetrachloride in l9 ml of benzene was added to a cooled solution of 4.5 g of dibenzo[b,f]-thiepin-l0( l lH)-one in ml of benzene. After addition of 6.1 g of l-methylpiperazine, the resulting mixture was stirred at room temperature for 1 hour and heated at reflux for 15 hours. The reaction mixture was filtered. The collected material was washed with benzene. The filtrate and the washings were combined together and concentrated to give (4-methyll -piperaziny1)dibenzo[b,f]-thiepin. Oxalate, melting point 233C (decomp.).

E. 4.5 g of dibenzo[b,f]thiepin-10( 1 lH)-one in 20 ml of benzene was added dropwise to a mixture of 6.1 g of l-methylpiperazine and 1.9 g of titanium chloride in 100 ml of benzene. The reaction mixture was stirred at room temperature for l hour and heated at reflux for hours. The reaction mixture was filtered, and the washings were combined together and concentrated to give 10(4-methyl-1-piperazinyl)dibenzo[b,f]-thiepin. Maleate, melting point 221C.

F. A solution of 0.57 g of antimony trichloride in 15 ml of anhydrous benzene was added dropwise with stirring to a solution of 1.13 g of dibenzo[b,f]thiepin- 10(1 1H)-one and 4.5 g of l-methylpiperazine in 50 ml of anhydrous benzene. The reaction mixture was stirred at room temperature for 2.5 hours and heated at reflux for 6.5 hours with stirring. The precipitate was removed by filtration, and the filtrate was washed with water and concentrated. The residue was dissolved in ethanol and treated with maleic acid. The precipitate was collected by filtration and recrystallized from ethanol to give 10-(4-methyl-1-piperazinyl)-dibenzo[b,f]- thiepin maleate. Melting point 218 to 219C (decomp).

G. A solution of about 0.6 g of zirconium tetrachloride in 15 m1 of anhydrous benzene was added dropwise to a cooled solution of 1.13 g of dibenzo[b,f]thiepin-10(11H)-one and 4.5 g of l-methylpiperazine in 50 ml of anhydrous benzene. The reaction mixture was stirred at room temperature for 2.5 hours, heated at reflux with stirring for an additional 6.5 hours and then treated as described in (F) to give 0.1 g of l0-(4-methyl-l-piperazinyl)-dibenzo[b,f]thiepin maleate, melting point 219 to 220C (decomp.).

H. 0.6 g of 4-methy1piperazine in 6 ml of benzene was added to phenyl lithium which was prepared from 250 mg of lithium metal and 2.83 g of phenyl bromide in 25 ml of dry ether in accordance with the conventional method. The reaction mixture was stirred for 30 minutes at room temperature and thereafter the solvent was distilled off. The resultant residue was dissolved into 25 ml of dry benzene and this solution was added to 1.1 g ofdibenzo[b,f]thiepin-10(1 1H)-one. This was followed by the dropwise addition of 0.29 g of titanium tetrachloride in 10 ml of benzene. The mixture was stirred for 30 minutes at room temperature and then heated under reflux for 17 hours. After cooling, the reaction mixture was diluted with ether. The precipitating substance was filtered off, and the ether layer was washed with water and dried to give l0-(4-methy1-lpiperazinyl)dibenzo[b,flthiepin as oil. Maleate, M.P., 221C (decomp.).

I. A solution of 1.9 g of titanium tetrachloride in 10 ml of benzene was added dropwise over a one-hour period to a solution of 4.2 g of dibenz[b,f]oxepin- 10(1 lH)-one and 10.0 g of l-methylpiperazine in 10 ml of benzene kept below 10C. The resulting mixture was stirred at room temperature for 1 hour and heated at reflux for 20 hours with stirring. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized 14 from petroleum benzin to give 4.0 g of l0-(4-methyl-1- piperazinyl)dibenz[b,f]oxepin. M.P. 109 to 110C. Maleate, M.P. 201 to 202C (decomp.).

Other compounds which can be prepared in the substantially same manner as above include: 10(lpiperazinyl)dibenzo[b,f]thiepin (maleate), M.P. 198 to 199C (decomp.); 8-chloro-10-(1-piperaziny1)- dibenzo[b,f]thiepin,1.R. 3330 cm (=NH), 1610 cm C=C 2-chloro-10-(4-methy1-1-piperazinyl)- dibenzolbflthiepin (maleate), M.P. 239C (decomp.); 2-trifluoromethy1-10-( l-piperazinyl )-dibenzo[b,f]thiepin; 7-trif1uoromethyl-l0-(1-piperaziny1)-dibenzo[b,f]- thiepin; 8-trifluoromethy1-10-( l-piperazinyl)-dihenzo[b,f]thiepin; 2-trifluoromethy1-10-(4-methyl 1- piperaziny1-dibenzo[b,f]thieipin; 7-trifluoromethyl-10- (4-methyl-1-piperazinyl)dibenzo[b,f]thiepin (maleate), M.P. 233 to 234C; 8-trifluoromethyl-l0-(4- methyl-l -piperaziny1)dibenzo[b,f]thiepin; S-nitro- 1 0- l -piperaziny1)dibenzo[b,f]thiepin; 8-nitro-10-(4- methyl-piperazinyl)dibenzo[b,f]thiepin; 8-dimethylsulfamoyl-l0-(1-piperaziny1)dibenzo[b,f]thiepin; 8- ch1oro-10-(4-a1lyl-1-piperaziny1) dibenzo[b,f]thiepin; 8-ch1orol 0-[4-(2-propagy1)- 1 -piperaziny1]dibenzo[b,f]thiepin (maleate), M.P. 189 to 189.5C; 8- chloro-10-(4-acetyl-1-piperaziny1)dibenzo[b,f]thiepin, M.P. l98.5 to 199.5C', 8-ch1oro-( 4-ethyl-1- piperazinyl)dibenzo [b,f]thiepin (maleate), M.P. 232C; 8-chloro-10-(4-methy1-1-piperaziny1)dibenzo[b,f]thiepin (maleate), M.P. 234C; 8-methoxy-10- (1-piperaziny1)dibenzo[b,f]thiepin, M.P. 138 to 139.5C; 8-methoxy-10-(4-methy1-l-piperaziny1) dibenzo[b,f]thiepin (maleate), M.P. 221 to 222C (decomp. S-methoxyl0-(4-propyl 1 -piperazinyl dibenzolbflthiepin; 10-( 4-benzy1- l-piperazinyl )dibenzo[b,f]thiepin, M.P. 136 to 137C; (maleate), M.P. 231C (decomp. 10-[4-(3-benzyloxypropyl)-1- piperazinyl]dibenzo[b,f]thiepin (maleate), M.P. 188 to 189C (decomp. 10-piperidinodibenzo[b,f]thiepin, M.P. 118 to 119C; 10-(2,5-dimethy1-1-piperazinyl)- dibenzo[b,f]thiepin (maleate), M.P. 241C (decomp.); 8-chloro-10(2,5-dimethyll-piperazinyl dibenzolbflthiepin, M.P. 244C (decomp.); 8-methyl-l0- (2,4,5-trimethy1-1-piperaziny1)dibenzo[b,f]thiepin; 10- morpho1inodibenzo[b,f]thiepin, M.P. 136 to 138C; l0-(4-methyl-1-diazipiny1)dibenzo[b,f]thiepin (maleate), M.P. 193C (decomp.); 10(1-piperaziny1)- dibenz[b,f]oxepin, LR. 3300 cm" NH), 1608 cm C=C J; 8-ch1oro-10-( l-piperazinyl) dibenz[b,- f]oxepin, M.P. l81.5 to 182.5C; 8-chloro-l0-(4- methyl-1-piperaziny1)dibenz[b,f]oxepin (maleate M.P. 187C (decomp.); 8-methy1thio-10-(4-methyl-1- piperazinyhdibenzlb,f]oxepin (maleate), M.P. 198 to 199C (decomp. 8-methylthio-10-( 1-piperaziny1)dibenz [b,f,loxepin (maleate), M.P. 202 to 203C (decomp. 8-meth0xyl 0-( 1-pipcraziny1)dibenz[b,f]oxepin, M.P. 157 to 159C; (maleate), M.P. 191.5 to 192C (decomp. 8-methoxy-10-(4-propyl-1- piperazinyl )dibenz[b,f]oxepin; 8-ethy1-10-(4-methyl- 1-piperazinyl)dibenz[b,f]oxepin (maleate), M.P. 201 to 202C (decomp.); 8-methanesu1fonyl-10-(1- piperazinyl)dibenz[b,f]oxepin (maleate), M.P.. 225C (decomp. 8-ethyl-10( l -piperaziny1)dibenz[b,f]oxepin. LR. 3350 cm NH), 1613 cm" C=C S-methanesulfonyl-l0-t4-methy1-1-piperaziny1)dibenz [b.floxepin (maleate), M.P. 205 to 206C; 8-ch1oro- 10-(4-al1y1-1-piperaziny1)dibenz[b,f]oxepin (maleate M.P. 178 to 180C (decomp.); 8-methoxy-l0-(4-a1lyll-piperazinyl) dibenz[b,f]oxepin; 8-ethy1-10-(4-a1lyl-lfloxepin; S-ethyll ()-[4-( 2-acetoxypropyl l piperazinyl]dibenz[b,f]oxepin, M.P. 165 to 167C; 8-nitro-l0-[4-(2-acetoxypropyl)-1-piperazinyl]- dibenz[ bfloxepin; 8-chlorol()[4-( l-methyl-Z-acetoxyethyl l -piperazinyl ]dibenz[ bfloxepin; 8-chlorol[ 4 2-acetoxyethyl l -diazepinyl ]dibenz[ b,f]oxepin; l0-l4-(3,4,5-trimethoxybenzoyloxyethyl l piperazinyl]dibenz[b,f]oxepin; 8-chloro-10-[4-(3,4,5 trimethoxybenzoyloxyethyl l -piperazinyl ldibenzl b,- f]oxepin; S-tritluoromethyl-10-[4-( 3,4,5-trimethoxybenzoyloxyethyl 1 -piperazinyl ]dibenz[ b,f]oxepin; S-methyll 0-[4-( 2 acetoxyethyl l -piperazinyl]dibenzo[a,d]cycloheptene; -methyl-8-chloro-10-[4-(2- acetoxyethyl 1 -piperazinyl ]dibenzo[a,d ]cycloheptene (maleate). M.P. 197 to 197.5C; 5-methyl-l0-[4 l2- 3,4,5-trimethoxybenzoyloxy )propylll-piperazinyl ]dibenz[ bflazepine; 8-methoxyl0-[4-( 2-acetoxyethyl)-l-piperazinyl]dibenz[bfloxepin (maleate), M.P. l79 to 180C; S-methoxy-l0-[4-(2-isobutyryloxyethyl)-l-piperazinyljdibenz [b,f]oxepin (maleate), M.P. 175 to 177C; 8-methoxy-l0-[4-(2acetoxyethyl)-lpiperazinyl]dibenz[bfloxepin (maleate), M.P. l99 to 200C; B-methylthiol 0-[4-( Z-acetoxyethyl 1 pipcrazinylldibenzlbfloxepin, M.P. l79 to l80C. h

l0-[4-( 3-acetoxypropyl l -piperazinyl ]dibenz[ b,- floxepin (maleate). M.P. 193C, etc.

EXAMPLE 7 EXAMPLE 8 A. To a solution of 8-nitro-lO-(4-methyl-lpiperazinyl)dibenz[b,f]oxepin (l 1.2 g) in 99% ethanol 500 ml), there is added platinum oxide, and the resulting mixture is subjected to catalytic reduction under atmospheric pressure. When a theoretical amount of hydrogen gas is absorbed, the reaction is interrupted. The catalyst is separated by filtration. The filtrate is concentrated. The residue is crystallized from ethanol to give 8-aminol O(4-methyll -piperazinyl )dibenz[ b,- f]oxepin (10.3 g). M.P. 200.5 to 202C.

Other compounds which can be prepared in the substantially same manner as above include: 8-amino-l0- (l-piperazinyl)dibenz[b,f]oxepin, M.P. l9l to 192C; 8-amino-10-[4-(2-hydroxyethyl)-l-piperazinyl1- dibenz[b,f]oxepin, LR. 3320 cm (-OH), 1600 cm C=C etc.

EXAMPLE 9 A suitable formulation of tablets consists of:

Grams l l0-(4-Methyl-l-piperazinyl)- dibenrlhfloxepin l (2 l Lactose 70 (3) Starch 5 (4) Magnesium stearate 2 The active ingredient, lactose and starch are thoroughly mixed and granulated. For tableting, the magnesium stearate is added, mixed with the granules. and the mixture tableted on a rotary press. Use of this procedure produces 100 tablets each containing mg of the active ingredient.

EXAMPLE [0 Another suitable formulation of tablets consists of:

IO Grams [l] 8-Chloro-l0-| 44 Z-hydruxycthyljl -pipera1inyl|dihenzlhJ'lnxepin 2 (2) Maiinitnl 90 (3) Starch 6 (4) Magnesium stearate 2 The active ingredient, mannitol and starch are thoroughly mixed and granulated. For tableting, the magnesium stearate is added, mixed with granules, and the mixture tableted on a rotary press. Use of this procedure produces 100 tablets each containing mg of the active ingredient.

EXAMPLE 1 1 A suitable formulation of dragees consists of:

( l) K-Chlorol0[4-(Z-hydroxyethylll-pipcrazinyl ldibenlul bflthiepin |2,000 grams (2) Aerosil 4.500 grams (3) Mai/e starch 4,500 grams (4) Stcaric acid 700 grams (5) Ethanol 6.0 liters 3U (61 Gelatin 1,800 grams (7) Purified water 20.0 liters (8) Tale 600 grams (9) Magnesium steurate 375 grams From the above materials, there are prepared 600,000 cores each containing 20 mg of the active ingredient in a conventional manner.

EXAMPLE l2 4() A suitable formulation of suppositories consists of:

Grams l) il-Chloro-ltl-M-methyl' l piperazinyl )dihenzul bflthiepin 2.500 5 (2) Ethylcnediaminctetraacetic acid disodium salt dihydrate 900 (3| Witcpsol H l2 l24.l00

From the above materials, there are prepared 100,000 suppositories each containing 25 mg of the active ingredient in a conventional manner.

What is claimed is:

l. A compound selected from the group consisting of l0-( 4-( 2-hydroxyethyl)- l-piperazinyl )dibenz( b,f)oxe pin, 8-chlorol0-( 4-( 2-hydroxyethyl l -piperazinyl 5 dibenzo( b,f)oxepin, 8-chlorol 0-(4-( 2-acetoxyethyl l-piperazinyl )-dibenz( b,f)oxepin, 8-chlorol 0-( 4-( 3- hydroxypropyl l -piperazinyl )-dibenz(b,f)oxepin, 8- chlorol0-(4-( 3-acetoxypropyll -piperazinyl dibenz( b,f)oxepin, 8-methoxyl 0-(4-( Z-hydroxyethyl l-piperazinyl )-dibenz( b,f)oxepin, S-nitrol 0-(4-( 2- hydroxyethyU- l -piperazinyl)-dibenz( b,f)oxepin, nitrol 0-( 4-( 2-( 2-acetoxyethyl)- l -piperazinyl)- dibenz( b,f)oxepin, l0-(4-( 2-hydroxyethyl l piperazinyl)dibenz(b,f)thiepin and 8-chloro-l0-(4-(2- hydroxyethyl l -piperazinyl )dibenz( b,f)thiepin.

2. The compound of claim I which is 10-[4-(2- hydroxyethyl l -piperazinyl ]dibenz[b,f]oxepin.

3. The compound ofclaim l which is 8-chloro-10-[4- (2-hydroxyethyl)- l-piperazinyl l-dibenzol b,f]oxepin.

4. The compound of claim 1 which is 8-chloro-10-[4- (Z-acctox yethyl l -piperazinyl ]-dibcnz[ b,f]oxcpin.

5. The compound of claim 1 which is 8-chlorol ()-[4- (3-hydroxypropyl l -piperazinyl ]-dibcnz[ b,f]oxepin.

6. The compound of claim 1 which is 8-chloro-10-[4- (3-ucetoxypropyl l -piperazinyl ]-dibenz[b,f]oxepin.

7. The compound of claim 1 which is S-methoxy-lO- 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 10-(4(2-HYDROXYETHYL)-1PIPERAZINYL)DIBENZ(B)OXEPIN, 8-CHLORO10-(4-(2-HYDROXETHYL)-1-PIPERAZINYL)-DIBENZO(B,F)OXRPIN, 8-CHLORO-10-(4-(2-ACETOXYETHYL)-1-PIPERAZINYL)-DIBENZ(B,F)OXEPIN, 8-CHLORO-10-(4-(3-HYDROXYPROPYL)-1-PIPERAZINYL)DIBENZ(B,F)OXEPIN, 8-CHLORO-10-(4-(3-ACETOXYPROPYL-1 PIPERAZINYL)-DIBENZE(B,F)OXEPIN, 8-METHOXY-10-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL)-DIBENZ(B,F)OXEPIN, 8-NITOR-10-4-(2HYDORXYETHYL)-1-PIPERAZINYL)-DIBENZ(B,F)OXE (4-(2-ACETOXYETHYL)-1-PIPERAZINYL)DIBENZ(B,F)OXEPIN, 10 (4-(2-HYDROXYETHYL)-1-PIPERAZINYL)DIBENZ(B,F)THIEPIN AND 8-CHLORO-10-(4-(2-HYDROXYETHYL)-1-PIPERAZINYL(DIBEBZ(B.F)THIEPIN.
 2. The compound of claim 1 which is 10-(4-(2-hydroxyethyl)-1-piperazinyl)dibenz(b,f)oxepin.
 3. The compound of claim 1 which is 8-chloro-10-(4-(2-hydroxyethyl)-1-piperazinyl)-dibenzo(b,f)oxepin.
 4. The compound of claim 1 which is 8-chloro-10-(4-(2-acetoxyethyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 5. The compound of claim 1 which is 8-chloro-10-(4-(3-hydroxypropyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 6. The compound of claim 1 which is 8-chloro-10-(4-(3-acetoxypropyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 7. The compound of claim 1 which is 8-methoxy-10-(4-(2-hydroxyethyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 8. The compound of claim 1 which is 8-nitro-10-(4-(2-hydroxyethyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 9. The compound of claim 1 which is 8-nitro-10-(4-(2-(2acetoxyethyl)-1-piperazinyl)-dibenz(b,f)oxepin.
 10. The compound of claim 1 which is 10-(4-(2-hydroxyethyl)-1-piperazinyl)dibenz(b,f)thiepin.
 11. The compound of claim 1 which is 8-chloro-10-(4-(2-hydroxyethyl)-1-piperazinyl)dibenz(b,f)thiepin. 